How should estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status be assessed and used to guide treatment in breast cancer?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Educational purpose only • Exercise caution as content is pending human review
Article Review Status
Submitted
Under Review
Approved

Last updated: February 25, 2026 • View editorial policy

Personalize

Help us tailor your experience

Which best describes you? Your choice helps us use language that's most understandable for you.

Hormone Receptor Status in Breast Cancer: ER, PR, and HER2

All invasive breast cancers must have ER, PR, and HER2 status determined through immunohistochemistry (IHC) and/or in situ hybridization testing, as these biomarkers are the only validated markers that directly guide treatment decisions and impact mortality and quality of life. 1, 2

Essential Testing Requirements

What Must Be Tested

  • ER status: Required for all ductal carcinoma in situ (DCIS) and all invasive breast cancers 1
  • PR status: Required for all invasive breast cancers 1
  • HER2 status: Required for all newly diagnosed invasive breast cancers 1

When to Test

  • Core needle biopsy is mandatory before any treatment is initiated to ensure diagnosis of invasive disease and assess biomarkers 1
  • Testing should be performed on the initial diagnostic specimen with proper fixation to ensure optimal antigen preservation 1
  • Retesting is required on metastatic lesions when disease recurs, as receptor status may change (discordance occurs in 9-12% of cases) 1, 2, 3

Testing Methodology

ER and PR Assessment

  • IHC is the standard method for determining ER and PR status 1
  • Laboratories must validate their assay against clinically validated methods with ≥90% concordance for positive results and ≥95% concordance for negative results 1
  • Positive threshold: ≥1% of tumor cells with nuclear staining is considered positive per ASCO/CAP guidelines 1, 2
  • Standardized scoring systems (Allred score or H-score) should be used 1, 4

HER2 Assessment

Six FDA-approved methods exist for HER2 testing: 1

  1. IHC HercepTest (DAKO)
  2. IHC Pathway HER2 test (Ventana)
  3. INFORM HER2 FISH test (Ventana)
  4. PathVysion HER2 FISH test (Vysis)
  5. PharmaDX HER2 FISH test (DAKO)
  6. SPOT-Light HER2 CISH test (Invitrogen)

HER2-positive criteria (updated ASCO-CAP 2013): 1

  • IHC 3+ when >10% of cells (not 30%) show complete membrane staining
  • FISH positive if HER2 gene copies ≥6 or HER2/chromosome 17 ratio ≥2.0

Equivocal results require reflex testing: 1, 5

  • IHC 2+ requires FISH confirmation
  • FISH ratios 1.8-2.2 or gene copies 4-6 require additional testing with alternative method
  • Never treat equivocal HER2 as negative without confirmatory testing 5

Laboratory Quality Requirements

Accreditation and Validation

  • Only accredited laboratories should perform ER, PR, and HER2 testing 1
  • Laboratories must have standardized testing procedures and proficiency evaluation programs 1
  • Initial validation requires 95% concordance with clinically validated assays 1

Common Sources of Error

  • Interlaboratory variability: ER and PR reliability varies widely among laboratories due to diverse methodologies 1
  • False-positive and false-negative HER2 results are common in clinical practice 1
  • Decalcification of bone biopsies can affect IHC results, particularly for PR (33% major discrepancy rate) 6
  • Tumor heterogeneity may cause sampling errors and discordant results 2

Clinical Application

Treatment Decisions Based on Receptor Status

ER/PR-positive disease: 1, 2

  • Determines eligibility for endocrine therapy (tamoxifen, aromatase inhibitors)
  • Endocrine therapy is first-line for metastatic disease unless visceral crisis

HER2-positive disease: 1, 2, 7

  • Determines eligibility for HER2-targeted therapies (trastuzumab, pertuzumab, T-DM1, lapatinib)
  • Requires dual HER2 blockade (trastuzumab + pertuzumab) with chemotherapy for metastatic disease

Triple-negative disease (ER-/PR-/HER2-): 1, 2

  • Chemotherapy is primary systemic treatment option
  • Consider BRCA testing for PARP inhibitor eligibility

Managing Discordant Results

When primary and metastatic receptor status differ: 1, 2

  • Use the receptor status from the metastasis to direct therapy (ASCO panel informal consensus)
  • Consider clinical scenario and patient's goals for care
  • True biologic change versus tumor heterogeneity versus assay variability cannot always be differentiated

Pathology Report Requirements

Essential elements that must be included: 1

  • Tumor site and specimen type
  • Histologic type and grade
  • ER status with percentage of positive cells
  • PR status with percentage of positive cells
  • HER2 status (IHC score or FISH ratio/gene copies)
  • Fixation method and time
  • Up to 50% of pathology reports are missing critical elements 1

Critical Pitfalls to Avoid

  • Do not proceed with treatment if ER, PR, or HER2 results are missing or equivocal without resolution 5
  • Do not assume receptor status remains unchanged at recurrence—always retest metastatic lesions 1, 2
  • Do not use non-validated or non-FDA-approved tests for treatment decisions outside clinical trials 1, 2
  • If ER/PR/HER2 are negative on core biopsy, retest on surgical specimen to account for tumor heterogeneity 1
  • Ensure proper specimen orientation and communication between clinician and pathologist about biomarker testing requests 1

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Guideline

Biomarkers in Breast Cancer Prognostication and Treatment

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

4
Research

Immunochemistry for oestrogen receptor, progesterone receptor and HER2 on cell blocks in primary breast carcinoma.

Cytopathology : official journal of the British Society for Clinical Cytology, 2012

5
Guideline

Optimal Treatment for Metastatic ER/PR+ HER2 Equivocal Breast Cancer After CDK4/6 Inhibitor Progression

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

7
Guideline

Neoadjuvant Therapy for Stage IIIA HER2-Positive Breast Cancer

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

Related Questions

In patients with hormone‑receptor‑positive breast cancer, when is serum estradiol measurement indicated and is routine monitoring required?
How are estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status determined in breast cancer and how do they guide treatment?
Do grade III internal hemorrhoids cause a perceived rectal fullness that masks normal rectal fullness, and does hemorrhoidectomy relieve this sensation?
Interpret these echocardiogram findings: normal left ventricular systolic function with ejection fraction 71%, mildly increased left ventricular wall thickness, normal segmental wall motion, normal global longitudinal strain -25.7%, normal right ventricular systolic function (S' 14.4 cm/s, TAPSE 2.9 cm), septal flattening in mid to late diastole consistent with right ventricular volume overload, mildly enlarged right atrium, mild aortic regurgitation (pressure halftime 736 ms), moderate tricuspid regurgitation, severe pulmonary hypertension with estimated pulmonary arterial systolic pressure 62 mmHg, moderate pulmonic regurgitation, enlarged right ventricular outflow tract, dilated inferior vena cava with >50% collapse and elevated right atrial pressure 8 mmHg, and no pericardial effusion.
How do I write a prescription for estradiol vaginal suppository 10 µg (0.01 mg) with the appropriate dosing schedule and instructions?
Can Zoloft (sertraline) be prescribed for a patient with a platelet count of 113 × 10⁹/L?
In an asymptomatic patient with a small‑to‑moderate incidentally discovered arachnoid cyst and no neurologic deficits, what is the recommended management?
In a cirrhotic patient with new acute kidney injury, what empiric antibiotic coverage should be initiated?

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

Have a follow-up question?

Our Medical A.I. is used by practicing medical doctors at top research institutions around the world. Ask any follow up question and get world-class guideline-backed answers instantly.

Ask Question